Brigatinib

In vitro studies demonstrated that brigatinib is a substrate of CYP2C8. In healthy subjects, coadministration of multiple 600 mg twice daily doses of gemfibrozil, a strong CYP2C8 inhibitor, with a single 90 mg brigatinib dose reduced brigatinib C_max by 41%, AUC_0-INF by 12%, and AUC_0-120 by 15%, relative to a 90 mg brigatinib dose administered alone. The effect of gemfibrozil on the pharmacokinetics of brigatinib is not clinically meaningful and the underlying mechanism for the decreased exposure of brigatinib is unknown. No dose adjustment is required during coadministration with strong CYP2C8 inhibitors.

Moderate CYP3A inducers may decrease the AUC of brigatinib by approximately 50% based on simulations from a physiologically-based pharmacokinetic model. The concomitant use of moderate CYP3A inducers with brigatinib, including but not limited to efavirenz, modafinil, bosentan, etravirine, and nafcillin should be avoided.

In vitro studies in hepatocytes have shown that brigatinib is an inducer of CYP3A4. Clinical drug-drug interaction studies with sensitive CYP3A substrates have not been conducted. Brigatinib may reduce plasma levels of coadministered medicinal products that are predominantly metabolised by CYP3A. Therefore, coadministration of brigatinib with CYP3A substrates with a narrow therapeutic index (e.g., alfentanil, fentanyl, quinidine, cyclosporine, sirolimus, tacrolimus) should be avoided as their effectiveness may be reduced.

Grapefruit or grapefruit juice may also increase plasma concentrations of brigatinib and should be avoided.

Brigatinib is a substrate of P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP) in vitro. Given that brigatinib exhibits high solubility and high permeability, inhibition of P-gp and BCRP is not expected to result in a clinically meaningful change in the systemic exposure of brigatinib. No dose adjustment is required for brigatinib during coadministration with P-gp and BCRP inhibitors.

Coadministration of brigatinib with substrates of P-gp (e.g., digoxin, dabigatran, colchicine, pravastatin), BCRP (e.g., methotrexate, rosuvastatin, sulfasalazine), organic cation transporter 1 (OCT1), multidrug and toxin extrusion protein 1 (MATE1), and 2K (MATE2K) may increase their plasma concentrations. Patients should be closely monitored when Alunbrig is coadministered with substrates of these transporters with a narrow therapeutic index (e.g., digoxin, dabigatran, methotrexate).

In vitro studies demonstrated that brigatinib is a substrate of CYP3A4/5. In healthy subjects, coadministration of multiple 200 mg twice daily doses of itraconazole, a strong CYP3A inhibitor, with a single 90 mg brigatinib dose increased brigatinib C_max by 21%, AUC_0-INF by 101% (2-fold), and AUC_0-120 by 82% (<2-fold), relative to a 90 mg brigatinib dose administered alone.

The concomitant use of strong CYP3A inhibitors with brigatinib, including but not limited to certain antivirals (e.g., indinavir, nelfinavir, ritonavir, saquinavir), macrolide antibiotics (e.g., clarithromycin, telithromycin, troleandomycin), antifungals (e.g., ketoconazole, voriconazole), and nefazodone should be avoided. If concomitant use of strong CYP3A inhibitors cannot be avoided, the dose of brigatinib should be reduced by approximately 50% (i.e. from 180 mg to 90 mg, or from 90 mg to 60 mg). After discontinuation of a strong CYP3A inhibitor, brigatinib should be resumed at the dose that was tolerated prior to the initiation of the strong CYP3A inhibitor.

Moderate CYP3A inhibitors (e.g., diltiazem and verapamil) may increase the AUC of brigatinib by approximately 40% based on simulations from a physiologically-based pharmacokinetic model. No dose adjustment is required for brigatinib in combination with moderate CYP3A inhibitors. Patients should be closely monitored when brigatinib is coadministered with moderate CYP3A inhibitors.

In vitro studies demonstrated that brigatinib is a substrate of CYP3A4/5. In healthy subjects, coadministration of multiple 600 mg daily doses of rifampicin, a strong CYP3A inducer, with a single 180 mg brigatinib dose decreased brigatinib C_max by 60%, AUC_0-INF by 80% (5-fold), and AUC_0-120 by 80% (5-fold), relative to a 180 mg brigatinib dose administered alone. The concomitant use of strong CYP3A inducers with brigatinib, including but not limited to rifampicin, carbamazepine, phenytoin, rifabutin, phenobarbital, and St. John’s wort should be avoided.

A reduced starting dose of 60 mg once daily for the first 7 days, then 90 mg once daily is recommended for patients with severe renal impairment (eGFR <30 mL/min). Patients with severe renal impairment should be closely monitored for new or worsening respiratory symptoms that may indicate ILD/pneumonitis (e.g., dyspnoea, cough, etc.) particularly in the first week.

A reduced starting dose of 60 mg once daily for the first 7 days, then 120 mg once daily is recommended for patients with severe hepatic impairment (Child-Pugh class C).

No human data on the effect of brigatinib on fertility are available. Based on repeat-dose toxicity studies in male animals, brigatinib may cause reduced fertility in males. The clinical relevance of these findings to human fertility is unknown.

Hypertension has occurred in patients treated with brigatinib.

Blood pressure should be monitored regularly during treatment with brigatinib. Hypertension should be treated according to standard guidelines to control blood pressure. Heart rate should be monitored more frequently in patients if concomitant use of a medicinal product known to cause bradycardia cannot be avoided. For severe hypertension (≥ Grade 3), brigatinib should be withheld until hypertension has recovered to Grade 1 or to baseline. The dose should be modified accordingly.

Severe, life-threatening, and fatal pulmonary adverse reactions, including those with features consistent with ILD/pneumonitis, can occur in patients treated with brigatinib.

Most pulmonary adverse reactions were observed within the first 7 days of treatment. Grade 1-2 pulmonary adverse reactions resolved with interruption of treatment or dose modification. Increased age and shorter interval (less than 7 days) between the last dose of crizotinib and the first dose of brigatinib were independently associated with an increased rate of these pulmonary adverse reactions. These factors should be considered when initiating treatment with brigatinib. Patients with a history of ILD or drug-induced pneumonitis were excluded from the pivotal trials.

Some patients experienced pneumonitis later in treatment with brigatinib.

Patients should be monitored for new or worsening respiratory symptoms (e.g., dyspnoea, cough, etc.), particularly in the first week of treatment. Evidence of pneumonitis in any patient with worsening respiratory symptoms should be promptly investigated. If pneumonitis is suspected, the dose of brigatinib should be withheld, and the patient evaluated for other causes of symptoms (e.g., pulmonary embolism, tumour progression, and infectious pneumonia). The dose should be modified accordingly.

Elevations of amylase and lipase have occurred in patients treated with brigatinib. Lipase and amylase should be monitored regularly during treatment with brigatinib. Based on the severity of the laboratory abnormalities, treatment with brigatinib should be withheld, and the dose modified accordingly.

Bradycardia has occurred in patients treated with brigatinib. Caution should be exercised when administering brigatinib in combination with other agents known to cause bradycardia. Heart rate and blood pressure should be monitored regularly.

If symptomatic bradycardia occurs, treatment with brigatinib should be withheld and concomitant medicinal products known to cause bradycardia should be evaluated. Upon recovery, the dose should be modified accordingly. In case of life-threatening bradycardia, if no contributing concomitant medication is identified or in case of recurrence, treatment with brigatinib should be discontinued.

Elevations of hepatic enzymes (aspartate aminotransferase, alanine aminotransferase) and bilirubin have occurred in patients treated with brigatinib. Liver function, including AST, ALT and total bilirubin should be assessed prior to the initiation of brigatinib and then every 2 weeks during the first 3 months of treatment. Thereafter, monitoring should be performed periodically. Based on the severity of the laboratory abnormalities, treatment should be withheld, and the dose modified accordingly.

Elevations of CPK have occurred in patients treated with brigatinib. Patients should be advised to report any unexplained muscle pain, tenderness, or weakness. CPK levels should be monitored regularly during brigatinib treatment. Based on the severity of the CPK elevation, and if associated with muscle pain or weakness, treatment with brigatinib should be withheld, and the dose modified accordingly.

Elevations of serum glucose have occurred in patients treated with brigatinib. Fasting serum glucose should be assessed prior to initiation of brigatinib and monitored periodically thereafter. Antihyperglycaemic treatment should be initiated or optimised as needed. If adequate hyperglycaemic control cannot be achieved with optimal medical management, brigatinib should be withheld until adequate hyperglycaemic control is achieved; upon recovery reducing the dose may be considered or brigatinib may be permanently discontinued.

Visual disturbance adverse reactions have occurred in patients treated with brigatinib. Patients should be advised to report any visual symptoms. For new or worsening severe visual symptoms, an ophthalmologic evaluation and dose reduction should be considered.

Brigatinib may cause foetal harm when administered to a pregnant woman. Studies in animals have shown reproductive toxicity. There are no clinical data on the use of brigatinib in pregnant women. Brigatinib should not be used during pregnancy unless the clinical condition of the mother requires treatment. If brigatinib is used during pregnancy, or if the patient becomes pregnant while taking this medicinal product, the patient should be apprised of the potential hazard to a foetus.

It is unknown whether brigatinib is excreted in human milk. Available data cannot exclude potential excretion in human milk. Breast-feeding should be stopped during treatment with brigatinib.

Women of childbearing potential / Contraception in males and females

Women of childbearing age being treated with brigatinib should be advised not to become pregnant and men being treated with brigatinib should be advised not to father a child during treatment. Women of reproductive potential should be advised to use effective non-hormonal contraception during treatment with brigatinib and for at least 4 months following the final dose. Men with female partners of reproductive potential should be advised to use effective contraception during treatment and for at least 3 months after the last dose of brigatinib.

Fertility

No human data on the effect of brigatinib on fertility are available. Based on repeat-dose toxicity studies in male animals, brigatinib may cause reduced fertility in males. The clinical relevance of these findings to human fertility is unknown.

Brigatinib has minor influence on the ability to drive and use machines. However, caution should be exercised when driving or operating machines as patients may experience visual disturbance, dizziness, or fatigue while taking brigatinib.

Summary of the safety profile

The most common adverse reactions (≥25%) reported in patients treated with brigatinib at the recommended dosing regimen were increased AST, increased CPK, hyperglycaemia, increased lipase, hyperinsulinaemia, diarrhoea, increased ALT, increased amylase, anaemia, nausea, fatigue, hypophosphataemia, decreased lymphocyte count, cough, increased alkaline phosphatase, rash, increased APTT, myalgia, headache, hypertension, decreased white blood cell count, dyspnoea, and vomiting.

The most common serious adverse reactions (≥2%) reported in patients treated with brigatinib at the recommended dosing regimen other than events related to neoplasm progression were pneumonia, pneumonitis, dyspnoea and pyrexia.

Tabulated list of adverse reactions

The data described below reflect exposure to brigatinib at the recommended dosing regimen in three clinical trials: a Phase 3 trial (ALTA 1L) in patients with advanced ALK-positive NSCLC previously not treated with an ALK-inhibitor (N=136), a Phase 2 trial (ALTA) in patients treated with brigatinib with ALK-positive NSCLC who previously progressed on crizotinib (N=110), and a phase ½ dose escalation/expansion trial in patients with advanced malignancies (N=28). Across these studies, the median duration of exposure in patients receiving brigatinib at the recommended dosing regimen was 21.8 months.

Adverse reactions reported are presented in Table 1 and are listed by system organ class, preferred term and frequency. Frequency categories are very common (≥1/10), common (≥1/100 to <1/10) and uncommon (≥1/1,000 to <1/100). Within each frequency grouping, undesirable effects are presented in order of frequency.

Table 1. Adverse reactions reported in patients treated with brigatinib (per Common Terminology Criteria for Adverse Events (CTCAE) version 4.03) at the 180 mg regimen (N=274):

^† The frequencies for ADR terms associated with chemistry and haematology laboratory changes were determined based on the frequency of abnormal laboratory shifts from baseline.
^a Includes atypical pneumonia, pneumonia, pneumonia aspiration, pneumonia cryptococcal, lower respiratory tract infection, lower respiratory tract infection viral, lung infection
^b Includes Grade 5 events
^c Grade not applicable
^d Includes headache, sinus headache, head discomfort, migraine, tension headache
^e Includes paraesthesia, peripheral sensory neuropathy, dysaesthesia, hyperaesthesia, hypoaesthesia, neuralgia, neuropathy peripheral, neurotoxicity, peripheral motor neuropathy, polyneuropathy, burning sensation, post herpetic neuralgia
^f Includes altered visual depth perception, cataract, colour blindness acquired, diplopia, glaucoma, intraocular pressure increased, macular oedema, photophobia, photopsia, retinal oedema, vision blurred, visual acuity reduced, visual field defect, visual impairment, vitreous detachment, vitreous floaters, amaurosis fugax
^g Includes bradycardia, sinus bradycardia
^h Includes sinus tachycardia, tachycardia, atrial tachycardia, heart rate increased
ⁱ Includes blood pressure increased, diastolic hypertension, hypertension, systolic hypertension
^j Includes dyspnoea, dyspnoea exertional
^k Includes interstitial lung disease, pneumonitis
^l Includes abdominal discomfort, abdominal distension, abdominal pain, abdominal pain lower, abdominal pain upper, epigastric discomfort
^m Includes aphthous stomatitis, stomatitis, aphthous ulcer, mouth ulceration, oral mucosal blistering
ⁿ Includes dermatitis acneiform, erythema, exfoliative rash, rash, rash erythematous, rash macular, rash maculo-papular, rash papular, rash pruritic, rash pustular, dermatitis, dermatitis allergic, dermatitis contact, generalised erythema, rash follicular, urticaria, drug eruption, toxic skin eruption
° Includes pruritus, pruritus allergic, pruritus generalised, pruritus genital, vulvovaginal pruritus
^p Includes musculoskeletal pain, myalgia, muscle spasms, muscle tightness, muscle twitching, musculoskeletal discomfort
^q Includes asthenia, fatigue
^r Includes eyelid oedema, face oedema, oedema peripheral, periorbital oedema, swelling face, generalised oedema, peripheral swelling, angioedema, lip swelling, periorbital swelling, skin swelling, swelling of eyelid
^s Includes blood cholesterol increased, hypercholesterolemia

Description of selected adverse reactions

Pulmonary adverse reactions

In ALTA 1L, 2.9% of patients experienced any Grade ILD/pneumonitis early in treatment (within 8 days), with Grade 3-4 ILD/pneumonitis in 2.2% of patients. There were no fatal ILD/pneumonitis. Additionally, 3.7% of patients experienced pneumonitis later in treatment.

In ALTA, 6.4% of patients experienced pulmonary adverse reactions of any grade, including ILD/pneumonitis, pneumonia and dyspnoea, early in treatment (within 9 days, median onset: 2 days); 2.7% of patients had Grade 3-4 pulmonary adverse reactions and 1 patient (0.5%) had fatal pneumonia. Following Grade 1-2 pulmonary adverse reactions, treatment with brigatinib was either interrupted and then restarted or the dose was reduced. Early pulmonary adverse reactions also occurred in a dose escalation study in patients (N=137) (Study 101) including three fatal cases (hypoxia, acute respiratory distress syndrome and pneumonia). Additionally, 2.3% of patients in ALTA experienced pneumonitis later in treatment, with 2 patients having Grade 3 pneumonitis.

Elderly

Early pulmonary adverse reaction was reported in 10.1% of patients ≥65 years of age compared with 3.1% of patients <65 years of age.

Hypertension

Hypertension was reported in 30% of patients treated with brigatinib at the 180 mg regimen with 11% having Grade 3 hypertension. Dose reduction for hypertension occurred in 1.5% at the 180 mg regimen. Mean systolic and diastolic blood pressure, in all patients, increased over time.

Bradycardia

Bradycardia was reported in 8.4% of patients treated with brigatinib at the 180 mg regimen.

Heart rates of less than 50 beats per minute (bpm) were reported in 8.4% of patients at the 180 mg regimen.

Visual disturbance

Visual disturbance adverse reactions were reported in 14% of patients treated with brigatinib at the 180 mg regimen. Of these, three Grade 3 adverse reactions (1.1%) including macular oedema and cataract were reported.

Dose reduction for visual disturbance occurred in two patients (0.7%) at the 180 mg regimen.

Peripheral neuropathy

Peripheral neuropathy adverse reactions were reported in 20% of patients treated at the 180 mg regimen. Thirty-three percent of patients had resolution of all peripheral neuropathy adverse reactions. The median duration of peripheral neuropathy adverse reactions was 6.6 months, with a maximum duration of 28.9 months.

Creatine phosphokinase (CPK) elevation

In ALTA 1L and ALTA, elevations of CPK were reported in 64% of patients treated with brigatinib at the 180 mg regimen. The incidence of Grade 3-4 elevations of CPK was 18%. The median time to onset for CPK elevations was 28 days.

Dose reduction for CPK elevation occurred in 10% of patients at the 180 mg regimen.

Elevations of pancreatic enzymes

Elevations of amylase and lipase were reported in 47% and 54% of patients treated with brigatinib, respectively at the 180 mg regimen. For elevations to Grade 3 and 4, the incidences for amylase and lipase were 7.7% and 15%, respectively. The median time to onset for amylase elevations and lipase elevations was 17 days and 29 days, respectively.

Dose reduction for elevation of lipase and amylase occurred in 4.7% and 2.9% of patients, respectively at the 180 mg regimen.

Elevation of hepatic enzymes

Elevations of ALT and AST were reported in 49% and 68% of patients treated with brigatinib, respectively at the 180 mg regimen. For elevations to Grade 3 and 4, the incidences for ALT and AST were 4.7% and 3.6%, respectively.

Dose reduction for elevation of ALT and AST occurred in 0.7% and 1.1% of patients, respectively at the 180 mg regimen.

Hyperglycaemia

Sixty one percent of patients experienced hyperglycaemia. Grade 3 hyperglycemia occurred in 6.6% of patients.

No patients had dose reductions due to hyperglycaemia.